4-Methylpyrazole (also known as fomepizole or 4-MP) inhibits alcohol dehydrogenase (ADH), an enzyme that oxidizes alcohols as part of a two-step metabolic removal pathway in which ethanol is oxidized by ADH to acetaldehyde, which is in turn oxidized by aldehyde dehydrogenase (ALDH) to acetic acid. 4-MP has been approved by the U.S. Food and Drug Administration for the treatment of ethylene glycol or methanol poisoning. See, e.g., Scalley et al., American Family Physician 2002, 66, 807-812. This approved use of 4-MP requires high dose ranges, e.g., 20 mg/kg body mass initial dose, following by additional doses of 15 mg/kg every 12 hours, which are administered intravenously under the care of a physician.
Administration of doses of 4-MP below 10 mg/kg has been shown to be effective in treating ethanol intolerance or symptoms of aldehyde accumulation in subjects with reduced or absent ALDH activity who have consumed alcohol.
Patient compliance, for instance, with regard to administration of doses of 4-MP used to treat ethanol intolerance, could be improved by the development of formulations of 4-MP suitable for self-administration, in particular, oral administration. Further, it would be advantageous to have available solid formulations of 4-MP suitable for administration to subjects. Solid formulations are less prone to spillage and/or leakage than liquid formulations, are easier to package, and are easier to self-administer.
Preparation of solid formulations of 4-MP for administration to subjects that remain stable under storage conditions has proved difficult.
Thus, solid formulations comprising 4-MP, optionally in a unit dosage form, which are stable under storage conditions are sought.